Nitroglycerin (NG) has long been recognized as a vasodilator having utility in the treatment of, among other indications, angina pectoris and congestive heart failure. NG was originally administered either orally or buccally and more recently transdermally. Transdermal NG drug delivery can be effected either through application of a gel or ointment such as the Nitrobid.RTM. ointment to the skin or through the use of various commercially available transdermal NG delivery systems. A reasonably complete survey of the transdermal nitroglycerin products approved in the United States appears in an article entitled "Transdermal Drug Delivery", Curtis D. Black, Ph.D., U.S. Pharmacist, pages 49-78, November 1982. As indicated therein the approved transdermal NG delivery systems deliver NG at an average in vivo drug delivery rate of approximately 0.5 to 0.625 mg/cm.sup.2 /24 hrs, equivalent to approximately 20 to 26 .mu.g/cm.sup.2 hr. Another system, the Deponit system which has been approved in Europe, delivers NG at a rate of approximately 15 .mu.g/cm.sup.2 hr. Patents relating to such delivery systems include U.S. Pat. Nos. 4,191,015 and 3,742,951 and co-pending co-assigned patent application No. 278,364 filed June 29, 1981 for a Bandage for Administering Beneficial Drug, the corresponding South African Patent having been issued as African Pat. No. 82/0124, dated Dec. 29, 1982, all of the above U.S. Patents being incorporated herein by reference.
Although the approved products have received wide patient acceptance, the total daily NG dose obtained from these systems is not adequate to provide the substantial NG doses required in the treatment of congestive heart failure or recalcitrant cases of angina pectoris. In order to obtain the needed daily doses of greater than 40 mg, a multiplicity of the existing systems would have to be applied or systems of substantially increased surface areas developed, neither of which is considered acceptable by the patients. Although it has been suggested in U.S. Pat. Nos. 4,191,015 and 3,742,951 to increase transdermal NG delivery rates by the co-administration of a permeation enhancer and NG and U.S. Pat. No. 4,262,003 which is incorporated herein by reference discloses the controlled delivery of a permeation enhancer as a means of controlling the rate of drug delivery, we are unaware of any transdermal NG delivery system specifically designed to deliver NG transdermally at controlled in vivo fluxes greater than 40 .mu.g/cm.sup.2 hr and preferably in the range of 50 to 150 .mu.g/cm.sup.2 hr.
It is accordingly an object of this invention to provide a transdermal drug delivery system which is capable of delivering NG through intact skin at a controlled in vivo transdermal delivery rate of at least 40 .mu.g/cm.sup.2 hr for extended periods of time of at least about 16 hours and preferably 24 hours or even multiples thereof.
It is another object of this invention to provide a transdermal NG drug delivery system suitable for use in the treatment of angina pectoris.
It is another object of this invention is to provide a transdermal nitroglycerin drug delivery system suitable for use in congestive heart failure.
It is another object of this invention to provide a transdermal nitroglycerin delivery system for the co-administration of nitroglycerin and a skin permeation enhancer for nitroglycerin.